H2 Protects Against Lipopolysaccharide-Induced Cardiac Dysfunction via Blocking TLR4-Mediated Cytokines Expression.
Background and Purpose: Septic cardiomyopathy, which is one of the features of multi-organ dysfunction in sepsis, is characterized by ventricular dilatation, reduced ventricular contractility, and reduction in ejection fraction and, if severe, can lead to death. To date, there is no specific therapy that exists, and its treatment represents a large unmet clinical need. Herein, we investigated the effects and underlying anti-inflammatory mechanisms of hydrogen gas in the setting of lipopolysaccharide (LPS)-induced cardiomyocytes injury. Experimental Approach: Hydrogen gas was intraperitoneally injected to mice in LPS plus hydrogen group and hydrogen group for 4 days. On fourth, LPS was given by intraperitoneal injection to mice in LPS group and to mice in LPS plus hydrogen group. In addition, H9c2 cardiomyocytes were treated with hydrogen-rich medium for 30 min before LPS. The transthoracic echocardiography was performed at 6 h post-LPS to assess left ventricular end-systolic diameter (LVESD), left ventricular end-diastolic diameter (LVEDD), left ventricular ejection fraction (EF%), fractional shortening (FS%), left ventricular mass average weight (LV mass AW), and LV mass AW (Corrected). The histological and morphological analyses of left ventricular were performed by hematoxylin and eosin (H&E) staining and Masson's trichrome staining. The mRNA levels of ANP and BNP were examined by PCR in vitro. The expression of cytokines were assayed by Enzyme Linked Immunosorbent Assay (ELISA) and PCR. Moreover, Western blotting was performed to examine the expression of TLR4, the activation of ERK1/2, p38, JNK, and the expression of NF-κB in nucleus after 6 h of LPS challenge in vivo and in vitro. Key Results: LPS induced cardiac dysfunction; hydrogen therapy improved cardiac function after LPS challenge. Furthermore, pretreatment with hydrogen resulted in cardioprotection during septic cardiomyopathy via inhibiting the expression of pro-inflammatory cytokines TNFα, IL-1β, and IL-18; suppressing the phosphorylation of ERK1/2, p38, and JNK; and reducing the nuclear translocation of NF-κB and the expression of TLR4 by LPS. Conclusion and Implications: Hydrogen therapy prevents LPS-induced cardiac dysfunction in part via downregulation of TLR4-mediated pro-inflammatory cytokines expression.


Ramucirumab in the second-line for patients with hepatocellular carcinoma and elevated alpha-fetoprotein: patient-reported outcomes across two randomised clinical trials.
Symptoms of advanced hepatocellular carcinoma (HCC) represent a substantial burden for the patient and are important endpoints to assess when evaluating treatment. Patient-reported outcomes were evaluated in subjects with advanced HCC and baseline alpha-fetoprotein (AFP) ≥400 ng/mL treated with second-line ramucirumab. Patients with AFP≥400 ng/mL enrolled in the REACH or REACH-2 phase 3 studies were used in this analysis. Eligible patients had advanced HCC, Child-Pugh A, Eastern Cooperative Oncology Group performance status 0/1 and prior sorafenib. Patients received ramucirumab 8 mg/kg or placebo once every 2 weeks. Disease-related symptoms and health-related quality of life (HRQoL) were assessed with the Functional Assessment of Cancer Therapy Hepatobiliary Symptom Index (FHSI)-8 and EuroQoL-5-Dimensions (EQ-5D) instruments, respectively. Time to deterioration (TTD) (≥3-point decrease in FHSI-8 total score;≥0.06-point decrease in EQ-5D score, from randomisation to first date of deterioration) was determined using Kaplan-Meier estimation and the Cox proportional hazards model. Both separate and pooled analyses for REACH AFP≥400 ng/mL and REACH-2 patients were conducted. In the pooled population with AFP ≥400 ng/mL (n=542; ramucirumab, n=316; placebo, n=226), median TTD in FHSI-8 total score was prolonged with ramucirumab relative to placebo (3.3 vs 1.9 months; HR 0.725; (95% CI 0.559 to 0.941); p=0.0152), including significant differences in back pain (0.668; (0.497 to 0.899); p=0.0044), weight loss (0.699; (0.505 to 0.969); p=0.0231) and pain (0.769; (0.588 to 1.005); p=0.0248) symptoms. TTD in EQ-5D score was not significantly different between ramucirumab and placebo groups (median 2.9 vs 1.9 months). Results in the individual trials were consistent with these findings. Ramucirumab in second-line treatment of advanced HCC demonstrates consistent benefit in the delay of deterioration in disease-related symptoms with no worsening of HRQoL. Taken with previously demonstrated ramucirumab-driven survival benefits in this setting, these data may inform patient-clinician discussions about the benefit-risk profile of this therapy. NCT01140347; NCT02435433, NCT02435433.


Inorganic nitrite attenuates NADPH oxidase-derived superoxide generation in activated macrophages via a nitric oxide-dependent mechanism.
Oxidative stress contributes to the pathogenesis of many disorders, including diabetes and cardiovascular disease. Immune cells are major sources of superoxide (O2(∙-)) as part of the innate host defense system, but exaggerated and sustained O2(∙-) generation may lead to progressive inflammation and organ injuries. Previous studies have proven organ-protective effects of inorganic nitrite, a precursor of nitric oxide (NO), in conditions manifested by oxidative stress and inflammation. However, the mechanisms are still not clear. This study aimed at investigating the potential role of nitrite in modulating NADPH oxidase (NOX) activity in immune cells. Mice peritoneal macrophages or human monocytes were activated by lipopolysaccharide (LPS), with or without coincubation with nitrite. O2(∙-) and peroxynitrite (ONOO(-)) formation were detected by lucigenin-based chemiluminescence and fluorescence techniques, respectively. The intracellular NO production was measured by DAF-FM DA fluorescence. NOX isoforms and inducible NO synthase (iNOS) expression were detected by qPCR. LPS increased both O2(∙-) and ONOO(-) production in macrophages, which was significantly reduced by nitrite (10µmol/L). Mechanistically, the effects of nitrite are (1) linked to increased NO generation, (2) similar to that observed with the NO donor DETA-NONOate, and (3) can be abolished by the NO scavenger carboxy-PTIO or by the xanthine oxidase (XO) inhibitor febuxostat. Nox2 expression was increased in activated macrophages, but was not influenced by nitrite. However, nitrite attenuated LPS-induced upregulation of iNOS expression. Similar to that observed in mice macrophages, nitrite also reduced O2(∙-) generation in LPS-activated human monocytes. In conclusion, XO-mediated reduction of nitrite attenuates NOX activity in activated macrophages, which may modulate the inflammatory response.


Assessing Spatial Learning and Memory in Small Squamate Reptiles.
Clinical research has leveraged a variety of paradigms to assess cognitive decline, commonly targeting spatial learning and memory abilities. However, interest in the cognitive processes of nonmodel species, typically within an ecological context, has also become an emerging field of study. In particular, interest in the cognitive processes in reptiles is growing although experimental studies on reptilian cognition are sparse. The few reptilian studies that have experimentally tested for spatial learning and memory have used rodent paradigms modified for use in reptiles. However, ecologically important aspects of the physiology and behavior of this taxonomic group must be taken into account when testing for spatially based cognition. Here, we describe modifications of the dry land Barnes maze and associated testing protocol that can improve performance when probing for spatial learning and memory ability in small squamate reptiles. The described paradigm and procedures were successfully used with male side-blotched lizards (Uta stansburiana), demonstrating that spatial learning and memory can be assessed in this taxonomic group with an ecologically relevant apparatus and protocol.


Conjugated eicosapentaenoic acid inhibits vascular endothelial growth factor-induced angiogenesis by suppressing the migration of human umbilical vein endothelial cells.
We have previously shown that conjugated eicosapentaenoic acid (CEPA), which is prepared by alkaline treatment of eicosapentaenoic acid and contains conjugated double bonds, suppresses tumor growth in vivo. In this earlier study, blood vessels were observed on the tumor surface in control mice, whereas in CEPA-treated mice, no such vessels were observed and the inner part of the tumor was discolored. These observations suggest that CEPA might suppress cancer cell growth through malnutrition due to a suppressive effect on tumor angiogenesis. In this study, the antiangiogenic effects of CEPA were investigated in vitro. CEPA at 5 micromol/L inhibited vascular endothelial growth factor (VEGF)-stimulated tube formation by human umbilical vein endothelial cells (HUVEC) (P < 0.05) and also inhibited VEGF-stimulated migration of HUVEC at a concentration of CEPA that suppressed tube formation (P < 0.05) but did not influence cell proliferation. The antiangiogenic mechanism of CEPA was investigated in vitro by measuring the secretion and expression of well-characterized angiogenic factors associated with cell migration, such as matrix metalloproteinases (MMP). CEPA at a concentration that suppressed tube formation inhibited secretion and mRNA expression of MMP2 and MMP9 in VEGF-stimulated HUVEC (P < 0.05). Our findings suggest that CEPA has potential use as a therapeutic dietary supplement for minimizing tumor angiogenesis.


Crosslinking of proteins to DNA in human nuclei using a 60 femtosecond 266 nm laser.
We developed appropriate conditions to use a laser with 60 femtosecond pulses, a frequency of 1 KHz and a wavelength of 266 nm to efficiently crosslink proteins to DNA in human nuclei for the purpose of using immunoprecipitation to study the binding of specific proteins to specific sequences of DNA under native conditions. Irradiation of nuclei for 30 min with 1-3 GW/cm(2)pulses crosslinked 10-12% of total protein to DNA. The efficiency of crosslinking was dose and protein specific. Histones H1 and H3 were crosslinked by 15 min of irradiation with 20-25% efficiency, at least 10 times more strongly than the other histones, consistent with experiments using conventional UV light. Irradiation for 15 min did not damage proteins, as assayed by SDS-PAGE of Ku-70 and histones. Although the same level of irradiation did not cause double-strand breaks, it did make the DNA partially insensitive to Eco RI restriction enzyme, probably through formation of thymidine dimers. Immuno-analysis of crosslinked nucleoprotein showed that Ku crosslinking to nuclear DNA is detectable only in the presence of breaks in the DNA, and that nucleosomes are bound to a significant fraction of the telomeric repeat (TTAGGG) (n).


DJ-1 (PARK7) mutations are less frequent than Parkin (PARK2) mutations in early-onset Parkinson disease.
Mutations in the Parkin gene (PARK2) are the most commonly identified cause of recessively inherited early-onset Parkinson disease (EOPD) but account for only a portion of cases. DJ-1 (PARK7) was recently reported as a second gene associated with recessively inherited PD with a homozygous exon deletion and a homozygous point mutation in two families. To investigate the frequency of DJ-1 mutations, the authors performed mutational analysis of all six coding exons of DJ-1 in 100 EOPD patients. For the detection of exon rearrangements, the authors developed a quantitative duplex PCR assay. Denaturing high performance liquid chromatography analysis was used to screen for point mutations and small deletions. Further, Parkin analysis was performed as previously described. The authors identified two carriers of single heterozygous loss-of-function DJ-1 mutations, including a heterozygous deletion of exons 5 to 7 and an 11-base pair deletion, removing the invariant donor splice site in intron 5. Interestingly, both DJ-1 mutations identified in this study were found in the heterozygous state only. The authors also detected a polymorphism (R98Q) in 1.5% of the chromosomes in both the patient and control group. In the same patient sample, 17 cases were detected with mutations in the Parkin gene. Mutations in DJ-1 are less frequent than mutations in Parkin in EOPD patients but should be considered as a possible cause of EOPD. The effect of single heterozygous mutations in DJ-1 on the nigrostriatal system, as described for heterozygous changes in Parkin and PARK6, remains to be elucidated.


Initial Glycemic Control and Care Among Younger Adults Diagnosed With Type 2 Diabetes.
The prevalence of type 2 diabetes is increasing among adults under age 45. Onset of type 2 diabetes at a younger age increases an individual's risk for diabetes-related complications. Given the lasting benefits conferred by early glycemic control, we compared glycemic control and initial care between adults with younger onset (21-44 years) and mid-age onset (45-64 years) of type 2 diabetes. Using data from a large, integrated health care system, we identified 32,137 adults (aged 21-64 years) with incident diabetes (first HbA1c ≥6.5% [≥48 mmol/mol]). We excluded anyone with evidence of prior type 2 diabetes, gestational diabetes mellitus, or type 1 diabetes. We used generalized linear mixed models, adjusting for demographic and clinical variables, to examine differences in glycemic control and care at 1 year. Of identified individuals, 26.4% had younger-onset and 73.6% had mid-age-onset type 2 diabetes. Adults with younger onset had higher initial mean HbA1c values (8.9% [74 mmol/mol]) than adults with onset in mid-age (8.4% [68 mmol/mol]) (P < 0.0001) and lower odds of achieving an HbA1c <7% (<53 mmol/mol) 1 year after the diagnosis (adjusted odds ratio [aOR] 0.70 [95% CI 0.66-0.74]), even after accounting for HbA1c at diagnosis. Adults with younger onset had lower odds of in-person primary care contact (aOR 0.82 [95% CI 0.76-0.89]) than those with onset during mid-age, but they did not differ in telephone contact (1.05 [0.99-1.10]). Adults with younger onset had higher odds of starting metformin (aOR 1.20 [95% CI 1.12-1.29]) but lower odds of adhering to that medication (0.74 [0.69-0.80]). Adults with onset of type 2 diabetes at a younger age were less likely to achieve glycemic control at 1 year following diagnosis, suggesting the need for tailored care approaches to improve outcomes for this high-risk patient population.


Serum leptin and age-related macular degeneration.
Leptin, a 167-amino acid protein secreted by adipocytes, has been shown to reduce beta-amyloid deposition and intracellular lipid concentration in animal models, two key pathogenic mechanisms underlying aging. We examined the association between serum leptin levels and AMD. We conducted a population-based case-control study including Chinese and Indian adults aged 40 to 80 years who participated in the Singapore Epidemiology of Eye Diseases Study (2007-2011). Age-related macular degeneration was assessed from retinal photographs graded using a modified Wisconsin Age-Related Maculopathy Grading System (n = 426; early = 389, late = 37). Controls (n = 927) without AMD were frequency matched for age, sex, and ethnicity. Serum leptin levels were measured using direct sandwich ELISA. Participants with AMD had lower levels of leptin compared with those without (mean [SD] = 10.0 [11.5] ng/mL versus 12.9 [16.4] ng/mL; P = 0.001). Mean levels of leptin among those with late, early, and without AMD were 8.8, 10.1, and 12.9 ng/mL (P trend = 0.005). In multivariable models adjusting for potential confounders, including smoking, body mass index, blood pressure, and high-density lipoprotein cholesterol, increasing quartiles of leptin were associated with lower odds of AMD, odds ratio (95% confidence interval) of AMD was 0.56 (0.34-0.92) comparing highest to lowest quartile of serum leptin. In subgroup analyses, the inverse association between leptin and AMD was significant in women, Indian ethnicity, and ex-smokers. Higher serum leptin levels were inversely associated with AMD. These findings, if confirmed in prospective studies, may provide insights into new pathogenic pathways and possibly therapeutic targets in AMD.


Finger movement at birth in brachial plexus birth palsy.
To investigate whether the finger movement at birth is a better predictor of the brachial plexus birth injury. We conducted a retrospective study reviewing pre-surgical records of 87 patients with residual obstetric brachial plexus palsy in study 1. Posterior subluxation of the humeral head (PHHA), and glenoid retroversion were measured from computed tomography or Magnetic resonance imaging, and correlated with the finger movement at birth. The study 2 consisted of 141 obstetric brachial plexus injury patients, who underwent primary surgeries and/or secondary surgery at the Texas Nerve and Paralysis Institute. Information regarding finger movement was obtained from the patient's parent or guardian during the initial evaluation. Among 87 patients, 9 (10.3%) patients who lacked finger movement at birth had a PHHA > 40%, and glenoid retroversion < -12°, whereas only 1 patient (1.1%) with finger movement had a PHHA > 40%, and retroversion < -8° in study 1. The improvement in glenohumeral deformity (PHHA, 31.8% ± 14.3%; and glenoid retroversion 22.0° ± 15.0°) was significantly higher in patients, who have not had any primary surgeries and had finger movement at birth (group 1), when compared to those patients, who had primary surgeries (nerve and muscle surgeries), and lacked finger movement at birth (group 2), (PHHA 10.7% ± 15.8%; Version -8.0° ± 8.4°, P = 0.005 and P = 0.030, respectively) in study 2. No finger movement at birth was observed in 55% of the patients in this study group. Posterior subluxation and glenoid retroversion measurements indicated significantly severe shoulder deformities in children with finger movement at birth, in comparison with those lacked finger movement. However, the improvement after triangle tilt surgery was higher in patients who had finger movement at birth.


Tension and compression in the cytoskeleton of PC 12 neurites.
We report in this article that the retraction of PC 12 neurites, unlike that of other cultured neurons, is due to tension within the neurite. Retraction is rapid and independent of metabolic energy. Transection of one arm of a branched neurite immediately causes the remaining arm to take up a new equilibrium position between attachment points. Similarly, detachment of one growth cone of a cell causes the cell body to move to a new equilibrium position between the remaining neurites. These observations provide direct evidence for the suspension of the cell soma among a network of tensioned neurites. We used retraction as an assay for neurite tension to examine the role of actin filaments and microtubules in neurite support and elongation. Our data suggest that microtubules (MTs) within PC 12 neurites are under compression, supporting tension within the actin network. Treatment of cells with drugs that disrupt actin networks, cytochalasin D or erythro-9-[3-(2-hydroxynonyl)]adenosine eliminates retraction regardless of the absence of MTs, lack of adhesion to the substratum, or integrity of the neurite. Conversely, stimulation of actin polymerization by injection of phalloidin causes retraction of neurites. Treatments that depolymerize MTs, nocodazole or cold, cause retraction of neurites, which suggests that microtubules support this tension, i.e., are under compression. Stabilization of MTs with taxol stabilizes neurites to retraction and under appropriate circumstances can drive neurite extension. Taxol-stimulated neurite extension is augmented by combined treatment with anti-actin drugs. This is consistent with the actin network's normally exerting a force opposite that of MT assembly. Cytochalasin and erythro-9-[3-(2-hydroxynonyl)] adenosine were found to increase slightly the dose of nocodazole required for MT depolymerization. This is consistent with the postulated balance of forces and also suggests that alteration of the compression borne by the microtubules could serve as a local regulator for MT polymerization during neurite outgrowth.


Rapid and specific high-performance liquid chromatography for the in vitro quantification of D-Lys6-GnRH in a microemulsion-type formulation in the presence of peptide oxidation products.
A high-performance liquid chromatography (HPLC) method for assay of d-Lys(6)-GnRH contained in a microemulsion-type formulation is described. The peptide is extracted from the microemulsion matrix and quantified using a two-step gradient method. Separation from microemulsion compounds and potential peptide oxidation products was achieved on a Jupiter C(18) column at 40 degrees C, using a gradient of 10-35% CH(3)CN for peptide elution. The correlation of peak intensity measured at 220 nm and peptide concentration was linear over the range 2.5-60 microg/mL with a correlation coefficient of 0.9997 and a y-intercept not significantly different from zero (p > 0.05). Intraday and interday variability of the assay was less than 5% for multiple injections of samples containing 7.5, 30 and 60 microg/mL. The lower limit of quantitation was calculated to be 0.38 microg/mL, and the lower limit of detection was 0.13 microg/mL. The assay was applied to samples that were stressed under physiological conditions (37 degrees C, pH 7.4) over 4 days. Three degradation peaks were well resolved from the parent peptide, demonstrating the selectivity of the assay. Off-line MALDI TOF mass spectrometry was applied to identify these degradation species as oxidation products of the peptide.


Matrilineal genetic structure and female-mediated gene flow in red grouse (Lagopus lagopus scoticus): an analysis using mitochondrial DNA.
DNA sequence variation at the hypervariable 5' end of the mitochondrial control region was examined in 247 individuals to detect genetic divergence among 14 populations of red grouse (Lagopus lagopus scoticus) in northeastern Scotland. Ten haplotypes were resolved, several of which were shared among populations. Analysis of molecular variance, Nei's gamma ST, and a cladistic estimate of the amount of gene flow indicated a lack of overall population differentiation. Patterns of overall panmixia are in stark contrast to previous reports of localized subdivision among the same set of populations detected using hypervariable microsatellite markers. Because grouse cocks are territorial and show extreme natal philopatry and females are the dispersing sex, such discordance could be explained by sex-biased dispersal, with extensive female-mediated gene flow preventing mitochondrial DNA divergence. However, it is difficult to reconcile how effective dispersal of females would not homogenize both mitochondrial and nuclear structure simultaneously. We use a model that examines the spatial and temporal dynamics of diparentally and uniparentally inherited genes to show that, under realistic ecological scenarios and with specific differences in the dispersal of males and females, the local effective size of the nuclear genome can be less than that of the mitochondrial and the patterns of structuring we observe are meaningful.


Mechanisms of mitogen-activated protein kinase activation by nicotine in small-cell lung carcinoma cells.
We have previously reported that nicotine stimulates cell proliferation of three small-cell lung carcinoma (SCLC) cell lines by activating nicotinic receptors of the neuronal type. Here we report that, in the GLC-8 SCLC cell line, nicotine stimulates mitogen-activated protein (MAP) kinase activity in a concentration- and time-dependent manner (ED50 = 10 nM). The nicotine effect was antagonized by mecamylamine, an antagonist specific for neuronal nicotinic receptors. The absence of extracellular Ca2+, or pretreatment with pertussis toxin or the tyrosine kinase inhibitor genistein inhibited the action of nicotine on MAP kinase. Moreover, supernatants from nicotine-stimulated cells transferred to cells pretreated with mecamylamine were still capable of activating MAP kinase. On the other hand, the same supernatants transferred to cells pretreated with mecamylamine and pertussis toxin or genistein failed to activate MAP kinase. These findings suggest that nicotine elicits its stimulatory effect on MAP kinase in SCLC cells indirectly by inducing the production and/or release of a factor which then acts via a pertussis toxin- and tyrosine kinase-sensitive route.


Noncanonical role of Hox14 revealed by its expression patterns in lamprey and shark.
Hox genes are arranged in uninterrupted clusters in vertebrate genomes, and the nested patterns of their expression define spatial identities in multiple embryonic tissues. The ancestral Hox cluster of vertebrates has long been thought to consist of, maximally, 13 Hox genes. However, recently, Hox14 genes were discovered in three chordate lineages, the coelacanth, cartilaginous fishes, and amphioxus, but their expression patterns have not yet been analyzed. We isolated Hox14 cDNAs from the Japanese lamprey and cloudy catshark. These genes were not expressed in the central nervous systems, somites, or fin buds/folds but were expressed in a restricted cell population surrounding the hindgut. The lack of Hox14 expression in most of the embryonic axial elements, where nested Hox expressions define spatial identities, suggests a decoupling of Hox14 genes' regulation from the ancestral regulatory mechanism. The relaxation of preexisting constraint for collinear expression may have permitted the secondary losses of this Hox member in the tetrapod and teleost lineages.


Dietary factors in the aetiology of gastrointestinal cancer.
Gastrointestinal cancers, mainly oesophageal, gastric, pancreatic and large bowel cancer, account for about 40,000 deaths annually in England and Wales which is 32% of all cancer deaths. Nutritional factors have been implicated in the cause of each cancer and probably act by promoting the effect of carcinogenic substances taken in the diet or produced in the gut. Gastric cancer for example may be due to nitrosamine production in the stomach. This is enhanced by readily available sources of dietary nitrite and nitrate whilst the reaction is inhibited by vitamin C and low temperatures (2 degrees C). By contrast large bowel cancer can be related to high fat and meat intakes whilst a protective role for dietary fibre has been suggested. Dietary factors in the aetiology of oesophageal cancer differ from one high incidence area to another.


Production and characterization of isotype-specific monoclonal antibodies to bovine brain Rab GDI.
Small GTPases of the Rab family play a key role in controlling vesicular transport, and the Rab GDP-dissociation inhibitor (GDI) is a regulatory protein for the Rab proteins. Here we report the production and characterization of isotype-specific monoclonal antibodies (MAbs) to Rab GDI. Rab GDI was purified from bovine brain in several steps of column chromatography and was injected into BALB/c mice intraperitoneally. The resulting MAbs specifically recognized a single protein band of 55 kDa, which comigrates with purified bovine Rab GDI. To localize Rab GDI, we processed cells from different sources for indirect immunofluorescence microscopy. Interestingly, the MAb stained cytosol and vesicular structures in brain cells, whereas it predominantly stained cytosol in nonbrain cells. Next, we investigated the cross-reactivities of brain Rab GDI from some mammals. The immunoreactive bands on Western blots appeared to be the same in molecular mass, 55 kDa, in all mammalian species tested including human. In summary, we produced a panel of MAbs that are GDI-alpha/1 form-specific and we believe that the MAbs will be valuable tools in elucidating the function of Rab GDI isoforms.


Comparative analysis of early perioperative outcomes following radical cystectomy by either the robotic or open method.
We analyzed early perioperative outcomes following radical cystectomy by the robotic method compared with the conventional open method. All relevant clinical information was entered in a Microsoft Access Database and queried. P < 0.05 were considered statistically significant. The study cohort comprised 37 consecutive patients undergoing radical cystectomy; 24 (64.9%) cases were performed by the conventional open method and 13 (29.7%) by the robotic method. Body mass index, age, sex, blood transfusion rate, and median decrease in hemoglobin were comparable between the 2 groups. The robotic method resulted in significantly lower median estimated blood loss, shorter hospital stay, and longer operating time compared with the open group (P < 0.05). Four (16.7%) perioperative complications occurred in the open group compared with 2 (15.4%) in the robotic group (P = 1.0). The incidence of organ-confined (< or =T2N0Mx) disease was 9 (37.5%) and 7 (53.8%) in the open and robotic groups, respectively (P = 0.49). Radical cystectomy by the robotic method produces early perioperative results comparable to those of the open method. Although intraoperative estimated blood loss and hospital stay were significantly lower in the robotic group, operative time was longer which likely reflects our early operative experience with radical cystectomy by the robotic method.


Clinical characteristics of Long COVID patients presenting to a dedicated academic post-COVID-19 clinic in Central Texas.
Post-acute sequelae SARS-CoV-2 (PASC), also known as Long COVID, is a complex and widely recognized illness with estimates ranging from 5 to 30% of all COVID-19 cases. We performed a retrospective chart review of patients who presented to a dedicated Post-COVID-19 clinic between June 2021 and May 2022. The median patient age was 44.5 years, 63.5% patients were female, and patients presented at a median of 10.4 months from acute COVD-19 infection. 78% self-identified their race as white, and 21% identified as Latino ethnicity. During the acute COVID-19 infection, 50% of patients experienced moderate disease severity and 10.5% were hospitalized. The top three co-morbid conditions prior to SARS-CoV-2 infection included mental health conditions, hypertension and asthma. Patients reported a median of 18 new symptoms following COVID-19 illness, the most common were fatigue (89%), forgetfulness or "brain fog" (89%), and difficulty concentrating (77%). MoCA (Montreal Cognitive Assessment) assessment demonstrated that 46% had mild cognitive dysfunction. PHQ-9 (Patient Health Questionnaire) testing revealed 42% had moderate to severe depression, and 38% had moderate to severe anxiety on the GAD-7 (Generalized Anxiety Disorder) assessment. Symptom burden was similar across gender, age, and initial disease severity. PASC patients presenting to an academic Post-COVID-19 clinic experienced numerous multisystem symptoms and functional impairment, independent of the initial COVID-19 disease severity.


Hypertension: the rediscovery of combination therapy.
Awareness and treatment of hypertension in the United States has been improving for older patients, but hypertension continues in many cases to be poorly controlled. Three options exist if initial therapy fails to achieve target blood pressure: upward drug titration, substituting another drug, or combination drug therapy. Combination therapy is the attempt to optimize blood pressure control by using two or more agents with additive or synergistic effects. Problems with this approach include noncompliance due to complicated regimens, adverse drug reactions, and the added expense of multiple medications. However, the newer fixed-dose combination products have been shown to offer improved blood pressure control, simplification of drug regimens, decreased adverse reactions, improved compliance, and cost-effectiveness.


Injection of Antibodies against Immunodominant Epitopes Tunes Germinal Centers to Generate Broadly Neutralizing Antibodies.
Broadly neutralizing antibodies are crucial for the control of many life-threatening viral infections like HIV, influenza, or hepatitis. Their induction is a prime goal in vaccine research. Using computer simulations, we identify strategies to promote the generation of broadly neutralizing antibodies in natural germinal center (GC) reactions. The simulations predict a feedback loop based on antibodies and memory B cells from previous GC reactions that promotes GCs to focus on new epitopes. Memory-derived or injected antibodies specific for immunodominant epitopes control epitope availability, suppress the participation of memory B cells in the GC reaction, and allow for the evolution of other B cells to affinity mature for hidden or rare epitopes. This defines a natural selection mechanism for GC B cells to concentrate on new epitopes rather than refine affinity to already-covered epitopes. This principle can be used for the design and testing of future therapies and vaccination protocols.


Validation of a quality-of-life questionnaire for patients with pituitary adenoma.
The purpose of this study was to develop and validate a self-administered questionnaire to measure the health-related quality of life of patients with pituitary adenoma. A patient-centred iterative process, involving a literature review and focus group interviews with 84 patients, was used to develop a preliminary 106-item questionnaire and to validate it. The final questionnaire comprised the 30 most important items chosen by 20 patients and 17 items considered important by health care professionals. For assessment of its validity and reliability, 55 patients were asked to complete the final questionnaire, RAND-36, FACT- G/FACT-Br, and Karnofsky Performance Scale (KPS). Concurrent validity of the results of our questionnaire with those of the other instruments was assessed with Pearson correlation coefficients. Known-group validity for the scores of extreme groups was assessed with a Student's t test. Test-retest reliability was determined with Pearson correlation coefficients and a Student's t test for two sets of scores obtained one month apart. Forty-seven (85.5%) of the 55 questionnaires were completed. Our questionnaire was well correlated with the RAND-36, the FACT-Br, the FACT-G, and the KPS in the general health domain, but not with the KPS overall. Extreme groups (n = 20) were significantly different. Test-retest reliability (n = 24) was 0.88, and scores one month apart were not significantly different. Our patient-centred health-related quality of life questionnaire developed for patients with pituitary adenoma had good validity and reliability. This questionnaire could be used as a patient-centred outcome measure in clinical trials and for assessment of disease progression.


Real-world causal evidence for planned predictive enrichment in critical care trials: A scoping review.
Randomised clinical trials in critical care are prone to inconclusiveness due, in part, to undue optimism about effect sizes and suboptimal accounting for heterogeneous treatment effects. Although causal evidence from rich real-world critical care can help overcome these challenges by informing predictive enrichment, no overview exists. We conducted a scoping review, systematically searching 10 general and speciality journals for reports published on or after 1 January 2018, of randomised clinical trials enrolling adult critically ill patients. We collected trial metadata on 22 variables including recruitment period, intervention type and early stopping (including reasons) as well as data on the use of causal evidence from secondary data for planned predictive enrichment. We screened 9020 records and included 316 unique RCTs with a total of 268,563 randomised participants. One hundred seventy-three (55%) trials tested drug interventions, 101 (32%) management strategies and 42 (13%) devices. The median duration of enrolment was 2.2 (IQR: 1.3-3.4) years, and 83% of trials randomised less than 1000 participants. Thirty-six trials (11%) were restricted to COVID-19 patients. Of the 55 (17%) trials that stopped early, 23 (42%) used predefined rules; futility, slow enrolment and safety concerns were the commonest stopping reasons. None of the included RCTs had used causal evidence from secondary data for planned predictive enrichment. Work is needed to harness the rich multiverse of critical care data and establish its utility in critical care RCTs. Such work will likely need to leverage methodology from interventional and analytical epidemiology as well as data science.


Refractory epilepsy: clinical overview.
The incidence of refractory epilepsy remains high despite the influx of many new antiepileptic drugs (AEDs) over the past 10 years. Epidemiological data indicate that 20-40% of the patients with newly diagnosed epilepsy will become refractory to treatment. Factors that may be used to predict whether or not a patient will respond favorably to AED therapy include the type of epilepsy, underlying syndrome, etiology, and the patient's history of seizure frequency, density, and clustering. Environmental factors, such as trauma and prior drug exposure, and genetic factors that predetermine the rate of absorption, metabolism, and uptake of a drug by target tissue may also uniquely impact an individual and influence their response to AED therapy. Treatment resistance is, therefore, a multifaceted phenomenon. Since individuals with refractory epilepsy do not share a common reason for their treatment resistance, the use of targeted drug therapies may be our best option for improving treatment outcomes in this patient population. Pharmacogeneticists are currently attempting to understand the genetic basis of refractory epilepsy so that they can identify subgroups of patients who share a common genetic background and then target drug therapies to meet their specific needs.


Mitigating risks of students use of study drugs through understanding motivations for use and applying harm reduction theory: a literature review.
As postsecondary students' use of "study drugs" becomes more popular with increasingly reported negative effects on health and academic performance, failing prohibitionist policies to reduce consumption, and ambiguity in literature towards best practices to address this population, we present a literature review that seeks effective solutions educational institutions can apply to improve outcomes for students who use drugs. Motivations for use, effects of the substances, an analysis of efforts to control use from educational institutions, and suggestions on promoting most effective outcomes based on harm reduction, are described. Theory, quantitative, and qualitative works from systematic reviews, cohort studies, and epidemiological assessments are examined on the "study drugs" methylphenidate, dextroamphetamine, and amphetamine, also known as Adderall, Ritalin, Focalin, and Concerta. There is a focus on postsecondary students ages 18-25 in North America. Results show important risk factors for drug use including low perceived self-efficacy or enjoyment in courses, poor accommodation of special needs, reliance on external validation, having a low GPA, and experiencing a mental health issue. There is much misconception on the health and academic effects of these drugs in literature, among students, and on online knowledge sources. We suggest these drugs do not improve GPA and learning, while they might temporarily increase memory, but with detrimental negative health effects. Campaigns that address underlying factors of use can be most successful in mitigating harms.


[Translation of poly U by ribosomes from rel+ and rel- E. coli strains].
A translation of polyU in a cell-free system from CP78 (relA+) and CP79 (relA-) E. coli strains is investigated. The strains studied no not differ in misreading at Mg2+ concentration of 20 mM and concentrations of 16 mM (optimal for phenylalanine incorporation) and 18-22 mM (optimal for leucine incorporation) respectively. It is found that leucine incorporation increases similarly in both strains under conditions simulating an amino acid deficience (in phenylalanine-free incubation medium): the ratio leucine(-phenylalanine)/leucine (+phenylalanine) is 3.5-4 at a concentration of enzymatic fraction protein being 15-30 mkg per example, and it is 2 st a concentration of enzymatic fraction of 60-180 mkg of protein. It is suggested that differences in activities of a number of enzymes under amino acid starvation in Rel+ and Rel- cells are not due to differences in the precision of mRNA translation, but depend on the activity of respective genes.


[Contribution of the pharmacists to self-care and primary care with nonprescription medications].
Peoples have been much concerned on their healthy life. Recently, many kinds of dietary supplements and food for specified health uses are distributed and consumed in large quantities. Concurrently, medical case insurance in Japan has been accommodating a lot of patients increasingly year by year, when the importance and enlightenment of self-care and primary care of people with nonprescription medications is proposed. The Pharmacists Law defines the responsibility of the pharmacists for the public health and welfare with medication and hygienic affairs. The recent pharmacy education for 6 years in Japan is likely to orient pharmaceutical care practice for contribution to the treatment of patients by appropriate management of medication. The multidisciplinary knowledge on medicines and diseases, and the patient consultation technique are required in the pharmacy practice. The contribution and accountability of the community pharmacists to self-care and primary care with nonprescription medications, as social needs, is expected. In this review, social responsibility on the treatment with nonprescription medications and their information provided by the community pharmacists in future is discussed.


DSNet: A Flexible Detect-to-Summarize Network for Video Summarization.
In this paper, we propose a Detect-to-Summarize network (DSNet) framework for supervised video summarization. Our DSNet contains anchor-based and anchor-free counterparts. The anchor-based method generates temporal interest proposals to determine and localize the representative contents of video sequences, while the anchor-free method eliminates the pre-defined temporal proposals and directly predicts the importance scores and segment locations. Different from existing supervised video summarization methods which formulate video summarization as a regression problem without temporal consistency and integrity constraints, our interest detection framework is the first attempt to leverage temporal consistency via the temporal interest detection formulation. Specifically, in the anchor-based approach, we first provide a dense sampling of temporal interest proposals with multi-scale intervals that accommodate interest variations in length, and then extract their long-range temporal features for interest proposal location regression and importance prediction. Notably, positive and negative segments are both assigned for the correctness and completeness information of the generated summaries. In the anchor-free approach, we alleviate drawbacks of temporal proposals by directly predicting importance scores of video frames and segment locations. Particularly, the interest detection framework can be flexibly plugged into off-the-shelf supervised video summarization methods. We evaluate the anchor-based and anchor-free approaches on the SumMe and TVSum datasets. Experimental results clearly validate the effectiveness of the anchor-based and anchor-free approaches.


Systematic narrative review of decision frameworks to select the appropriate modelling approaches for health economic evaluations.
In constructing or appraising a health economic model, an early consideration is whether the modelling approach selected is appropriate for the given decision problem. Frameworks and taxonomies that distinguish between modelling approaches can help make this decision more systematic and this study aims to identify and compare the decision frameworks proposed to date on this topic area. A systematic review was conducted to identify frameworks from peer-reviewed and grey literature sources. The following databases were searched: OVID Medline and EMBASE; Wiley's Cochrane Library and Health Economic Evaluation Database; PubMed; and ProQuest. Eight decision frameworks were identified, each focused on a different set of modelling approaches and employing a different collection of selection criterion. The selection criteria can be categorized as either: (i) structural features (i.e. technical elements that are factual in nature) or (ii) practical considerations (i.e. context-dependent attributes). The most commonly mentioned structural features were population resolution (i.e. aggregate vs. individual) and interactivity (i.e. static vs. dynamic). Furthermore, understanding the needs of the end-users and stakeholders was frequently incorporated as a criterion within these frameworks. There is presently no universally-accepted framework for selecting an economic modelling approach. Rather, each highlights different criteria that may be of importance when determining whether a modelling approach is appropriate. Further discussion is thus necessary as the modelling approach selected will impact the validity of the underlying economic model and have downstream implications on its efficiency, transparency and relevance to decision-makers.


Integrins in the development, function and dysfunction of the nervous system.
Integrin receptors mediate cell-cell and cell-extracellular matrix (ECM) interactions in many different cell types, including neuronal cells. Earlier studies have shown a clear role for integrins in axon extension and cell adhesion/migration in CNS inflammation. Here we summarize more recent work that shows integrin functions in many phases of neural development, from neuroblast migration to synapse formation. Integrins of the beta-1 and alpha-v family are widely expressed on neurons at many stages of development, and their activity is regulated. Integrins are also important in the adult nervous system, since they have been implicated in synaptic plasticity involved in memory and learning. In addition, several diseases of the nervous system appear to involve beta-1, beta-2, and alpha-v integrins on leukocytes and glial cells. Research challenges for the future include understanding functions of specific integrin heterodimers and identifying the relevant integrin ligands that function in the nervous system.


Cardiovascular Toxicity of Targeted Therapies for Cancer: An Overview of Systematic Reviews.
Several targeted therapies for cancer have been associated with cardiovascular toxicity. The evidence for this association has not been synthesized systematically nor has the quality of evidence been considered. We synthesized systematic review evidence of cardiovascular toxicity of individual targeted agents. We searched MEDLINE, Embase, and the Cochrane Database of Systematic Reviews for systematic reviews with meta-analyses of cardiovascular outcomes for individual agents published to May 2020. We selected reviews according to prespecified eligibility criteria (International Prospective Register of Systematic Reviews CRD42017080014). We classified evidence of cardiovascular toxicity as sufficient, probable, possible, or indeterminate for specific cardiovascular outcomes based on statistical significance, study quality, and size. From 113 systematic reviews, we found at least probable systematic review evidence of cardiovascular toxicity for 18 agents, including high- and all-grade hypertension for bevacizumab, ramucirumab, axitinib, cediranib, pazopanib, sorafenib, sunitinib, vandetanib, aflibercept, abiraterone, and enzalutamide, and all-grade hypertension for nintedanib; high- and all-grade arterial thromboembolism (includes cardiac and/or cerebral events) for bevacizumab and abiraterone, high-grade arterial thromboembolism for trastuzumab, and all-grade arterial thromboembolism for sorafenib and tamoxifen; high- and all-grade venous thromboembolism (VTE) for lenalidomide and thalidomide, high-grade VTE for cetuximab and panitumumab, and all-grade VTE for bevacizumab; high- and all-grade left ventricular ejection fraction decline or congestive heart failure for bevacizumab and trastuzumab, and all-grade left ventricular ejection fraction decline/congestive heart failure for pazopanib and sunitinib; and all-grade corrected QT interval prolongation for vandetanib. Our review provides an accessible summary of the cardiovascular toxicity of targeted therapy to assist clinicians and patients when managing cardiovascular health.


βγ-Crystallination Endows a Novel Bacterial Glycoside Hydrolase 64 with Ca2+-Dependent Activity Modulation.
The prokaryotic βγ-crystallins are a large group of uncharacterized domains with Ca2+-binding motifs. We have observed that a vast number of these domains are found appended to other domains, in particular, the carbohydrate-active enzyme (CAZy) domains. To elucidate the functional significance of these prospective Ca2+ sensors in bacteria and this widespread domain association, we have studied one typical example from Clostridium beijerinckii, a bacterium known for its ability to produce acetone, butanol, and ethanol through fermentation of several carbohydrates. This novel glycoside hydrolase of family 64 (GH64), which we named glucanallin, is composed of a βγ-crystallin domain, a GH64 domain, and a carbohydrate-binding module 56 (CBM56). The substrates of GH64, β-1,3-glucans, are the targets for industrial biofuel production due to their plenitude. We have examined the Ca2+-binding properties of this protein, assayed its enzymatic activity, and analyzed the structural features of the β-1,3-glucanase domain through its high-resolution crystal structure. The reaction products resulting from the enzyme reaction of glucanallin reinforce the mixed nature of GH64 enzymes, in contrast to the prevailing notion of them being an exotype. Upon disabling Ca2+ binding and comparing different domain combinations, we demonstrate that the βγ-crystallin domain in glucanallin acts as a Ca2+ sensor and enhances the glycolytic activity of glucanallin through Ca2+ binding. We also compare the structural peculiarities of this new member of the GH64 family to two previously studied members.IMPORTANCE We have biochemically and structurally characterized a novel glucanase from the less studied GH64 family in a bacterium significant for fermentation of carbohydrates into biofuels. This enzyme displays a peculiar property of being distally modulated by Ca2+ via assistance from a neighboring βγ-crystallin domain, likely through changes in the domain interface. In addition, this enzyme is found to be optimized for functioning in an acidic environment, which is in line with the possibility of its involvement in biofuel production. Multiple occurrences of a similar domain architecture suggest that such a "βγ-crystallination"-mediated Ca2+ sensitivity may be widespread among bacterial proteins.


Pedagogical strategies used in clinical medical education: an observational study.
Clinical teaching is a complex learning situation influenced by the learning content, the setting and the participants' actions and interactions. Few empirical studies have been conducted in order to explore how clinical supervision is carried out in authentic situations. In this study we explore how clinical teaching is carried out in a clinical environment with medical students. Following an ethnographic approach looking for meaning patterns, similarities and differences in how clinical teachers manage clinical teaching; non-participant observations and informal interviews were conducted during a four month period 2004-2005. The setting was at a teaching hospital in Sweden. The participants were clinical teachers and their 4th year medical students taking a course in surgery. The observations were guided by the aim of the study. Observational notes and notes from informal interviews were transcribed after each observation and all data material was analysed qualitatively. Seven pedagogical strategies were found to be applied, namely: 1) Questions and answers, 2) Lecturing, 3) Piloting, 4) Prompting, 5) Supplementing, 6) Demonstrating, and 7) Intervening. This study contributes to previous research in describing a repertoire of pedagogical strategies used in clinical education. The findings showed that three superordinate qualitatively different ways of teaching could be identified that fit Ramsden's model. Each of these pedagogical strategies encompass different focus in teaching; either a focus on the teacher's knowledge and behaviour or the student's behaviour and understanding. We suggest that an increased awareness of the strategies in use will increase clinical teachers' teaching skills and the consequences they will have on the students' ability to learn. The pedagogical strategies need to be considered and scrutinized in further research in order to verify their impact on students' learning.


Dual-targeted polyplexes: one step towards a synthetic virus for cancer gene therapy.
Incorporating ligands into nano-scale carriers for specific delivery of therapeutic nucleic acids to tumor sites is a promising approach in anti-cancer strategies. Current artificial vector systems however still suffer from efficient and specific delivery, compared to their natural counterparts and addressed receptor types rarely are exclusively expressed on target cells. In this study synthetic dual receptor targeted polyplexes were developed, mimicking biphasic cell entry characteristics of natural viruses to increase efficiency and specificity by a dual-receptor internalization mechanism. For engineering the synthetic dual targeted vector system, the transferrin targeting peptide B6 was evaluated for the first time in the context of PEGylated PEI based polyplexes. As a second ligand, arginine-glycine-aspartic acid (RGD) containing peptide was incorporated for simultaneous integrin targeting. Cellular association, cellular uptake, transfection efficiency and accordant competition experiments displayed specificity of both ligands for each targeted receptor in two prostate cancer cell lines. A clear synergy of dual targeting over the combination of single-targeted polyplexes was found, suggesting that the dual targeting strategy is one step towards safe vectors for therapeutic approaches.


Stimulation of liver 5-aminolaevulinate synthetase by drugs and its relevance to drug-induced accumulation of cytochrome P-450. Studies with phenylbutazone and 3,5-diethoxycarbonyl-1,4-dihydrocollidine.
The relevance of the stimulation of 5-aminolaevulinate synthetase to the accumulation of cytochrome P-450 after administration of drugs was examined in rats treated with phenylbutazone and with 3,5-diethoxycarbonyl-1,4-dihydrocollidine. 3,5-Diethoxycarbonyl-1,4-dihydrocollidine alone stimulated 5-aminolaevulinate synthetase without increasing the concentration of cytochrome P-450, whereas phenylbutazone alone increased the microsomal cytochrome P-450 without significantly affecting the activity of the enzyme. When the two drugs were given together both effects were found. It is concluded that if an increased amount of 5-aminolaevulinate and haem must be made to provide for the accumulation of cytochrome P-450, it need only be a small amount. It is also concluded from these findings that stimulation of the drug-metabolizing system on the one hand and marked enhancement of 5-aminolaevulinate synthetase activity and porphyria on the other are likely to result from different actions of the drugs. Evidence is presented suggesting that porphyrogenic drugs stimulate markedly the activity of 5-aminolaevulinate synthetase by lowering the concentration of haem in the liver, thereby decreasing the normal feedback control. With 3,5-diethoxycarbonyl-1,4-dihydrocollidine a rapid inhibition of mitochondrial ferrochelatase and of liver haem synthesis may be the primary mechanism involved.


Complexity in language learning and treatment.
To introduce a Clinical Forum focused on the Complexity Account of Treatment Efficacy (C. K. Thompson, L. P. Shapiro, S. Kiran, & J. Sobecks, 2003), a counterintuitive but effective approach for treating language disorders. This approach espouses training complex structures to promote generalized improvement of simpler, linguistically related structures. Three articles are included, addressing complexity in treatment of phonology, lexical-semantics, and syntax. Complexity hierarchies based on models of normal language representation and processing are discussed in each language domain. In addition, each article presents single-subject controlled experimental studies examining the complexity effect. By counterbalancing treatment of complex and simple structures across participants, acquisition and generalization patterns are examined as they emerge. In all language domains, cascading generalization occurs from more to less complex structures; however, the opposite pattern is rarely seen. The results are robust, with replication within and across participants. The construct of complexity appears to be a general principle that is relevant to treating a range of language disorders in both children and adults. While challenging the long-standing clinical notion that treatment should begin with simple structures, mounting evidence points toward the facilitative effects of using more complex structures as a starting point for treatment.


The context of caretaking in rural areas: family factors influencing the level of functioning of seriously mentally ill patients living at home.
After the deinstitutionalization of psychiatric hospitals, many families became primary caregivers for seriously mentally ill individuals. Mental health services became further reduced with the advent of managed care and reductions in health and mental health care. The dearth of community-care options often results in psychiatric patients being quickly stabilized in hospital units and discharged to live with their families. The lack of community resources is particularly acute in rural areas. Given these realities the current study sought to determine if family caretaking variables are related to patient outcomes. Family factors including the perception of burden, expressed emotion (EE), and primary caregivers' social support were tested in a model of caretaking that examines the relationship between these factors and patients' symptom expression and social and occupational functioning. The sample includes 49 predominantly African American families living in a rural area and with a chronically ill family member who had been previously diagnosed with a psychotic disorder. Primary caregivers and patients were interviewed using adapted measures of burden, EE, and social support. Patients were administered a revised version of the Brief Psychiatric Rating Scale. Results suggest less perceived burden, increased caregiver support and, to a lesser extent, EE explain approximately one-fifth of the variance in patient functioning. These results support previous research demonstrating the importance of family factors for seriously mentally ill patient outcomes. Results are discussed in terms of implications for assisting families in the current era of diminished resources.


Clinical research in head and neck reconstruction.
Reconstructive head and neck surgery is not unlike other surgical fields in its paucity of clinical research. Difficulties exist in the design and execution of surgical studies, and there are many challenges and limitations that must be addressed. In this article, the types of studies that make up head and neck reconstructive literature are reviewed, as well as the evolution toward the use of quality-of-life scales, which measure patients' satisfaction with their state of health and function.


A plasma polymerization technique to overcome cerebrospinal fluid shunt infections.
Prosthetic devices, mainly shunts, are frequently used for temporary or permanent drainage of cerebrospinal fluid. The pathogenesis of shunt infection is a very important problem in modern medicine and generally this is characterized by staphylococcal adhesion to the cerebrospinal fluid shunt surfaces. In this paper, the prevention of the attachment of test microorganism Staphylococcus epidermidis on the cerebrospinal fluid shunt surfaces by 2-hydroxyethylmethacrylate (HEMA) precursor modification in the plasma polymerization system, is reported. Different plasma polymerization conditions (RF discharge power 10-20-30 W, exposure time 5-10-15 min) were employed during the surface modification. The surface chemistry and topology of unmodified and modified shunts was characterized by x-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM) and atomic force microscopy (AFM). Also, static contact angle measurements were performed to state the change of surface hydrophilicity. All samples were tested in vitro with Staphylococcus epidermidis. A plasma-polymerized HEMA film (PP HEMA) was found to be an alternative simple method to decrease the microorganism attachment and create bacterial anti-fouling surfaces. The attachment of the model microorganism Staphylococcus epidermidis on the shunt surface modified by PP HEMA at 20 W and 15 min was reduced 62.3% if compared to the unmodified control surface of the shunt.


Accelerated and personalized therapy for heart failure with reduced ejection fraction.
Previously, guidelines recommended initiating therapy in patients with heart failure and reduced ejection fraction (HFrEF) in a sequence that follows the chronological order in which trials were conducted, with cautious up-titration of each treatment. It remains unclear whether this historical approach is optimal and alternative approaches may improve patient outcomes. The potential reductions in events that might result from (i) more rapid up-titration of therapies used in the conventional order (based on the chronology of the trials), and (ii) accelerated up-titration and using treatments in different orders than is conventional were modelled using data from six pivotal trials in HFrEF. Over the first 12 months from starting therapy, using a rapid up-titration schedule led to 23 fewer patients per 1000 patients experiencing the composite of heart failure hospitalization or cardiovascular death and seven fewer deaths from any cause. In addition to accelerating up-titration of treatments, optimized alternative ordering of the drugs used resulted in a further reduction of 24 patients experiencing the composite outcome and six fewer deaths at 12 months. The optimal alternative sequences included sodium-glucose cotransporter 2 inhibition and a mineralocorticoid receptor antagonist as the first two therapies. Modelling of accelerated up-titration schedule and optimized ordering of treatment suggested that at least 14 deaths and 47 patients experiencing the composite outcome per 1000 treated might be prevented over the first 12 months after starting therapy. Standard treatment guidance may not lead to the best patient outcomes in HFrEF, though these findings should be tested in clinical trials.


Core principles for involving people with dementia in research: innovative practice.
The Scottish Dementia Working Group Research Sub-group is part of the Scottish Dementia Working Group, an internationally renowned campaigning group of people with dementia. We co-created our core principles for involving people with dementia in research between September and December 2013. The principles address six areas: (i) how people with dementia are valued and involved in research, (ii) lived experience as valid knowledge, (iii) physical and emotional safety, (iv) accessibility of all aspects of research, (v) training for researchers and (vi) the impact of our experiences of time on research processes. Through our core principles, we challenge researchers across all disciplines to re-consider how we and other people with dementia are involved in research as well as how knowledge in dementia research is created.


Morphological profiles for first-year National Collegiate Athletic Association Division I football players.
We are aware of no published research in which the morphological profiles of first-year collegiate football players are characterized. In light of the known association between obesity and cardiovascular disease and recent data suggesting an increased frequency of obesity and early death in professional football players, we have compiled a morphological profile of 65 freshman and transfer recruits (age = 18.4 +/- 1.2 years) from a National Collegiate Athletic Association (NCAA) Division I football program. Measured variables included height (HT), body mass (BM), and body fat percentage (BF) (hydrostatic method). Body mass index (BMI) was calculated using HT and weight variables. Individuals were grouped by player position for descriptive statistical analysis. The means for all 65 players were as follows: HT = 189 +/- 7 cm, BM = 106.5 +/- 4.8 kg, BF = 15 +/- 7%, and BMI = 29.8 +/- 4.7. Mean data from these collegiate athletes were compared to recently published data from professional players. By comparison, the average HT, BM, BF, and BMI of the professional football athletes were 188 +/- 4 cm, 107 +/- 4.8 kg, 14 +/- 5%, and 30.1 +/- 1.9, respectively. While the average BMIs of the collegiate athletes in this study would be classified as overweight or obese, the BFs were found to be within an acceptable range for health status. These data provide important indicators of morphological characteristics and BM health risks of new football recruits at a Division I university. The data presented also provide an historical basis for (a) evaluating both the conditioning of first-year incoming athletes, (b) determining the physical development of the athletes as they progress through the training program, and (c) charting the morphological changes that occur in collegiate football throughout time that may contribute to increased health risks to the athletes.


Increasing water use efficiency along the C3 to C4 evolutionary pathway: a stomatal optimization perspective.
C4 photosynthesis evolved independently numerous times, probably in response to declining atmospheric CO2 concentrations, but also to high temperatures and aridity, which enhance water losses through transpiration. Here, the environmental factors controlling stomatal behaviour of leaf-level carbon and water exchange were examined across the evolutionary continuum from C3 to C4 photosynthesis at current (400 μmol mol(-1)) and low (280 μmol mol(-1)) atmospheric CO2 conditions. To this aim, a stomatal optimization model was further developed to describe the evolutionary continuum from C3 to C4 species within a unified framework. Data on C3, three categories of C3-C4 intermediates, and C4 Flaveria species were used to parameterize the stomatal model, including parameters for the marginal water use efficiency and the efficiency of the CO2-concentrating mechanism (or C4 pump); these two parameters are interpreted as traits reflecting the stomatal and photosynthetic adjustments during the C3 to C4 transformation. Neither the marginal water use efficiency nor the C4 pump strength changed significantly from C3 to early C3-C4 intermediate stages, but both traits significantly increased between early C3-C4 intermediates and the C4-like intermediates with an operational C4 cycle. At low CO2, net photosynthetic rates showed continuous increases from a C3 state, across the intermediates and towards C4 photosynthesis, but only C4-like intermediates and C4 species (with an operational C4 cycle) had higher water use efficiencies than C3 Flaveria. The results demonstrate that both the marginal water use efficiency and the C4 pump strength increase in C4 Flaveria to improve their photosynthesis and water use efficiency compared with C3 species. These findings emphasize that the advantage of the early intermediate stages is predominantly carbon based, not water related.


Surgical treatment for chronic radial head dislocation.
The treatment of chronic radial head dislocation remains controversial. High rates of redislocation and complications have been reported after surgery. In our view, correction of malalignment with ulnar osteotomy is the key to a good surgical result. Since 1975, twenty-two patients were treated surgically for chronic radial head dislocation at our hospital. The procedure consisted of open reduction of a dislocated radial head followed by radial and/or ulnar osteotomy, with or without reconstruction of the annular ligament or by reconstruction of the annular ligament alone. The ages of the patients ranged from four to twenty years. In 1991, we modified the surgical technique by performing an oblique ulnar osteotomy with angulation and elongation and rigid plate fixation. Bone-grafting at the osteotomy site was also performed if necessary. A cast was applied with the forearm in neutral rotation and was worn for two to four weeks. Nine patients were treated with this modified technique. The mean interval between the initial injury and the reconstructive surgery was ten months. There were no serious surgical complications. Of the thirteen patients treated before 1991, four had a good reduction and seven had redislocation. Seven patients had restricted forearm rotation postoperatively. Of the nine patients treated with the modified osteotomy since 1991, seven had a good reduction. Two patients, who had had slight radial head deformity preoperatively, had subluxation postoperatively. Two patients had restricted forearm rotation. Since we modified our technique for ulnar osteotomy, good reduction of the radial head has been achieved without causing serious contracture. Both angulation and elongation of the ulna are required to allow the radial head to reduce.


The First Survey of Forensically Important Entomofauna Collected from Medicolegal Autopsies in South Korea.
Forensic entomology applies insect evidence to legal problems such as the estimation of minimum postmortem interval (mPMI). For this purpose, knowledge of the insect fauna that are attracted to human cadavers in each geographic region is a prerequisite. Despite many studies investigating the insect fauna attracted to meat, there has been no survey of the entomofauna on human cadavers in the East Asian temperate climate zone, particularly in Korea. Therefore, this study reports the entomofauna collected from medicolegal autopsies in northeastern Seoul and its suburbs. Insect samples were collected from 35 medicolegal autopsies in 2010, 2011, and 2013. Molecular and morphological methods were utilized for taxonomic identification. Among 1398 individual samples belonging to 3 orders, 13 families, 18 genera, and 32 species, the dominant family and species were Calliphoridae and Lucilia sericata, respectively. Despite its limited scale, this study provides a snapshot of the general entomofauna that are attracted to human cadavers in this region.


Long-term changes in populations of rainforest birds in the Australia Wet Tropics bioregion: A climate-driven biodiversity emergency.
Many authors have suggested that the vulnerability of montane biodiversity to climate change worldwide is significantly higher than in most other ecosystems. Despite the extensive variety of studies predicting severe impacts of climate change globally, few studies have empirically validated the predicted changes in distribution and population density. Here, we used 17 years (2000-2016) of standardised bird monitoring across latitudinal/elevational gradients in the rainforest of the Australian Wet Tropics World Heritage Area to assess changes in local abundance and elevational distribution. We used relative abundance in 1977 surveys across 114 sites ranging from 0-1500m above sea level and utilised a trend analysis approach (TRIM) to investigate elevational shifts in abundance of 42 species. The local abundance of most mid and high elevation species has declined at the lower edges of their distribution by >40% while lowland species increased by up to 190% into higher elevation areas. Upland-specialised species and regional endemics have undergone dramatic population declines of almost 50%. The "Outstanding Universal Value" of the Australian Wet Tropics World Heritage Area, one of the most irreplaceable biodiversity hotspots on Earth, is rapidly degrading. These observed impacts are likely to be similar in many tropical montane ecosystems globally.


Factors influencing condom use among women in Ghana: an HIV/AIDS perspective.
Although in Ghana information on HIV infection and prevention, both in terms of quality and quantity, has increased considerably within the past few years, available literature indicates that behaviour change is yet to correspond with the amount of information and education provided. The objective of this study is to examine factors that influence condom use among women in Ghana in the context of HIV/AIDS prevalence. Data for this study are from the 2003 Ghana Demographic and Health Surveys (GDHS) and the study population (N=5 691) was analysed using logistic regression with the Health Belief Model (HBM) as an explanatory tool. The outcome variable for this study is condom use during last sexual intercourse. The HBM identifies perception of HIV/AIDS risks, awareness of its seriousness, knowledge about prevention, and confidence in condom use as predictors of safe sexual activity. Results show that the proportion of women reporting use of condoms remains tremendously low, in both the rural and urban areas. In the urban areas, only 15% of women reported having sex with condom during their last intercourse, whereas in the rural areas the proportion is even lower (10%). However, multivariate analyses based on the HBM components show that speaking with a partner about how to avoid AIDS (Odds Ratio = 1.63) and perceived benefits of using condoms (Odds Ratio = 1.54) are notable factors that predict condom use. Overall, the study points out that with the exception of perceived severity, the HBM can be applied to understand condom use among the study population. It will be important to emphasise all components of the HBM and empower women with condom negotiation skills.


Therapeutic Response of Metastatic Colorectal Cancer Harboring a KRAS Missense Mutation After Combination Chemotherapy With the EGFR Inhibitor Panitumumab.
Over the past decade, subset analyses of retrospective and prospective clinical studies have determined that KRAS-mutated metastatic colorectal cancers do not respond effectively to inhibition of epidermal growth factor receptor (EGFR) with the EGFR-targeting monoclonal antibodies cetuximab or panitumumab. Within the past few years, the scope of tested variants in the KRAS oncogene has expanded significantly, and testing of all RAS family genes has become more widely available in clinical laboratories. Expert consensus guidelines have recommended not using EGFR inhibitors in patients with KRAS-mutated tumors. However, with increasing identification of low-prevalence variants, it is conceivable that some RAS mutations do not provide equivalent resistance to EGFR inhibition compared with the most prevalent mutations at codons 12, 13, and 61. This report describes a case of a patient with metastatic colon cancer harboring the p.A59T variant of KRAS, with objective radiographic response (36% decrease per RECIST 1.1) and carcinoembryonic antigen biomarker response to panitumumab therapy given with FOLFIRI chemotherapy. We propose that A59T represents one potential exception to the guidelines that KRAS mutant tumors fail to respond to therapy with EGFR inhibitors, altering the paradigm of using this generalized approach.


A current perspective on medical informatics and health sciences librarianship.
The article offers a current perspective on medical informatics and health sciences librarianship. The authors: (1) discuss how definitions of medical informatics have changed in relation to health sciences librarianship and the broader domain of information science; (2) compare the missions of health sciences librarianship and health sciences informatics, reviewing the characteristics of both disciplines; (3) propose a new definition of health sciences informatics; (4) consider the research agendas of both disciplines and the possibility that they have merged; and (5) conclude with some comments about actions and roles for health sciences librarians to flourish in the biomedical information environment of today and tomorrow. Boundaries are disappearing between the sources and types of and uses for health information managed by informaticians and librarians. Definitions of the professional domains of each have been impacted by these changes in information. Evolving definitions reflect the increasingly overlapping research agendas of both disciplines. Professionals in these disciplines are increasingly functioning collaboratively as "boundary spanners," incorporating human factors that unite technology with health care delivery.


Specificity in rehabilitation of word production: a meta-analysis and a case study.
Speech production impairment is a frequent deficit observed in aphasic patients and rehabilitation programs have been extensively developed. Nevertheless, there is still no agreement on the type of rehabilitation that yields the most successful outcomes. Here, we ran a detailed meta-analysis of 39 studies of word production rehabilitation involving 124 patients. We used a model-driven approach for analyzing each rehabilitation task by identifying which levels of our model each task tapped into. We found that (1) all rehabilitation tasks are not equally efficient and the most efficient ones involved the activation of the two levels of the word production system: the phonological output lexicon and the phonological output, and (2) the activation of the speech perception system as it occurs in many tasks used in rehabilitation is not successful in rehabilitating word production. In this meta-analysis, the effect of the activation of the phonological output lexicon and the phonological output cannot be assessed separately. We further conducted a rehabilitation study with DPI, a patient who suffers from a damage of the phonological output lexicon. Our results confirm that rehabilitation is more efficient, in terms of time and performance, when specifically addressing the impaired level of word production.


Reliability and validity of the short Schema Mode Inventory (SMI).
This study presents a new questionnaire to assess schema modes: the Schema Mode Inventory (SMI). First, the construction of the short SMI (118 items) was described. Second, the psychometric properties of this short SMI were assessed. More specifically, its factor structure, internal reliability, inter-correlations between the subscales, test-retest reliability and monotonically increase of the modes were tested. This was done in a sample of N = 863 non-patients, Axis I and Axis II patients. Results indicated a 14-factor structure of the short SMI, acceptable internal consistencies of the 14 subscales (Cronbach alpha's from .79 to .96), adequate test-retest reliability and moderate construct validity. Certain modes were predicted by a combination of the severity of Axis I and II disorders, while other modes were mainly predicted by Axis II pathology. The psychometric results indicate that the short SMI is a valuable measure that can be of use for mode assessment in SFT.


Acute myocardial infarction in thrombotic microangiopathies--clinical characteristics, risk factors and outcome.
Acute myocardial infarction (AMI) has been reported and is associated with poor outcome in the course of thrombotic microangiopathies (TMA). However, data are very limited in regard to the clinical characteristics, risk factors and outcome of AMI during TMA. Furthermore, current AMI definitions based on troponins are more sensitive and specific to detect myocardial injury. We retrospectively analysed 74 consecutive patients with 78 TMA episodes. TMA was defined as platelets below 150 x 10(9)/l, haemolytic anaemia, elevated lactate dehydrogenase (LDH) and increased red cell fragmentation, and AMI as serum troponin I above 1 ng/ml with symptoms of myocardial ischaemia and/or appropriate electrocardiography (ECG) alterations. AMI occurred in 14 TMA episodes (18%) (9 non- and 5 ST-segment elevation AMI). AMI occurred 5+/-3 days after TMA diagnosis, predominately in clinically suspected thrombotic thrombocytopenic purpura (TTP) as TMA subtype. Independent risk factors for subsequent AMI were TTP (RR 2.2; 95% CI 1.1-5.6), and serum LDH above 1,000 U/l (RR 2.7; 95% CI 1.3-7.2) as well as serum troponin I above 0.20 ng/ml at TMA presentation (RR 13.5; 95% CI 2.6-86.8). LDH above 1,000 U/l together with troponin I above 0.20 ng/ml had a sensitivity of 86% (95% CI 60-96%) and a specificity of 95% (95% CI 86-98%) to predict AMI in the later course of TMA. AMI contributed substantially to morbidity causing left ventricular dysfunction in three of eight survivors and potentially accounted for the death in five of six non-survivors. AMI is an early, frequent and severe complication during TMA. AMI occurs especially in TTP, and serum LDH above 1,000 U/l in combination with serum troponin I above 0.20 ng/ml at TMA presentation are excellent predictors of subsequent AMI.


Cell-mediated immune responses to artificial food additives in chronic urticaria.
In some cases of chronic urticaria it is suspected that food additives such as tartrazine and sodium benzoate or salicylates may play a role in the pathogenesis of the condition. Since, at times, chronic urticaria may appear histologically similar to a mild cell-mediated immune response, the release of the T cell-derived lymphokine leucocyte inhibitory factor (LIF), in response to incubation with these additives and with acetylsalicylic acid (ASA), was measured in vitro using cells from normal controls, from patients with chronic urticaria with or without clinically associated additive sensitivity and from patients with asthma with or without associated ASA sensitivity. It was found that significant production of LIF occurred in response to tartrazine and sodium benzoate in those individuals with chronic additive induced urticaria. In addition, tartrazine caused LIF release from mononuclear cells of ASA-sensitive asthmatics. These results may indicate a possible role for additive-induced cell-mediated immune responses in the pathogenesis of some cases of chronic urticaria and suggest a potential diagnostic test for this condition.


In silico trials for treatment of acute ischemic stroke: Design and implementation.
An in silico trial simulates a disease and its corresponding therapies on a cohort of virtual patients to support the development and evaluation of medical devices, drugs, and treatment. In silico trials have the potential to refine, reduce cost, and partially replace current in vivo studies, namely clinical trials and animal testing. We present the design and implementation of an in silico trial for treatment of acute ischemic stroke. We propose an event-based modelling approach for the simulation of a disease and injury, where changes to the state of the system (the events) are assumed to be instantaneous. Using this approach we are able to combine a diverse set of models, spanning multiple time scales, to model acute ischemic stroke, treatment, and resulting brain tissue injury. The in silico trial is designed to be modular to aid development and reproducibility. It provides a comprehensive framework for application to any potential in silico trial. A statistical population model is used to generate cohorts of virtual patients. Patient functional outcomes are also predicted with a statistical model, using treatment and injury results and the patient's clinical parameters. We demonstrate the functionality of the event-based modelling approach and trial framework by running proof of concept in silico trials. The proof of concept trials simulate the same cohort of patients twice: once with successful treatment (successful recanalisation) and once with unsuccessful treatment (unsuccessful treatment). Ways to overcome some of the challenges and difficulties in setting up such an in silico trial are discussed, such as validation and computational limitations.


Masking of spatial frequency in visual memory depends on distal, not retinal, frequency.
Spatial frequency discrimination thresholds measured in a two-interval forced choice paradigm are virtually constant across inter-stimulus intervals ranging from 400 to 30,000 msec, demonstrating that an accurate representation of spatial frequency is maintained in short-term memory. This representation can be degraded by briefly flashing a grating during the retention interval. Moreover, this memory masking effect varies with the spatial frequency of the mask, suggesting that the mechanisms used to store spatial frequency in memory are similar to low-level visual filters. In this paper we replicate those previous findings and extend them by showing (1) that accurate memory for spatial frequency lasts as long as 1 min; (2) that memory masking is based on distal (c/cm), not retinal (c/deg), spatial frequency.


Predictors of physical violence against children in Rwanda: findings from a National Cross-Sectional Survey.
To address the challenges of limited national data on the prevalence and nature of violence experienced by children, Rwanda conducted, in 2015-2016, the first National Survey on Violence among female and male children and youth aged 13-24 years. To further contribute to these efforts to fill existing data gaps, we used the Rwanda survey data to assess the prevalence and predictors of physical violence (PV) in children aged 13-17. A nationally representative sample of 618 male and 492 female children were analysed. Nationally representative weighted descriptive statistics were used to analyse the prevalence of PV self-reported by children, and logistic regression models were applied to investigate its predictors. Sixty percent of all children, including 36.53% of male and 23.38% of female children, reported having experienced any form of PV in their lifetime. Additionally, 21.81% of male children and 12.73% of female children reported experiences of PV within twelve months before the survey date. Older children (OR: 0.53 [0.40-0.72]), female children (OR: 0.43 [0.31-0.58]), and children not attending school (OR: 0.48 [0.31-0.73]) were less likely to be physically abused. However, sexually active children (OR: 1.66 [1.05-2.63]), children in households from the middle wealth quintile (OR: 1.63 [1.08-2.47]), children living in a larger family (OR: 1.55 [1.07-2.26]), and children who reported not feel close to both biological parents (OR: 2.14 [1.31-3.49]) had increased odds of reporting physical violence. Higher rates of PV in children attending school were the key finding. There is an urgent need to design and implement particular national interventions to prevent and reduce the incidence of PV in schools in Rwanda. PV was also associated with poor parent-child relations. Parents and other adult caregivers should be sensitised to the consequences of PV on children and be urged to adopt positive parenting practices.


Suppression of inflammatory cytokines during ex vivo lung perfusion with an adsorbent membrane.
Lung grafts can be perfused ex vivo for 2 hours without edema formation; however, prolonged ex vivo lung perfusion (EVLP) eventually induces lung injury. This study evaluated the change in proinflammatory cytokines of the perfusate during EVLP and investigated the effect of cytokine removal using an adsorbent membrane. Porcine heart-lung blocks were harvested after electrically induced cardiac arrest and underwent 12-hour EVLP with an adsorbent membrane (membrane group: n = 5) and without an adsorbent membrane (control group: n = 6). In the control group, both tumor necrosis factor-alpha and interleukin 8 levels were elevated in the perfusate 2 hours after perfusion. Although tumor necrosis factor-alpha and interleukin 8 levels were significantly lower in the membrane group than in the control group during the EVLP period, there was no significant difference in oxygenation, pulmonary vascular resistance, edema formation, or myeloperoxidase activity between the two groups. Tumor necrosis factor-alpha and interleukin 8 levels of the perfusate were elevated during EVLP. Although adverse effects of these inflammatory cytokines were anticipated, removal of inflammatory cytokines by the adsorbent membrane did not improve lung function during prolonged EVLP. Factors other than the cytokines may play a major role in causing lung injury during EVLP. Further research is needed to investigate the real mechanism of lung graft injury during prolonged EVLP and to establish longer EVLP duration for graft treatment. This strategy could contribute to the salvage of potentially damaged lungs, especially from cardiac death donors, and to expansion of the donor pool.


Resolution of Cardiogenic Shock Using Echocardiography-Guided Pacing Optimization in Intensive Care: A Case Series.
Inotropic and vasopressor drugs are routinely used in critically ill patients to maintain adequate blood pressure and cardiac output in patients with cardiogenic shock although potentially at the expense of increasing myocardial oxygen demand. Pacing optimization has been demonstrated as effective in reducing catecholamine requirements in patients with chronic heart failure by improving cardiac efficiency; however, there are no reports relating to the effectiveness of pacemaker optimization on cardiac output in critically ill patients with cardiogenic shock in the intensive care. Retrospective data analysis. Twenty-bed adult tertiary cardiothoracic ICU, university hospital. Eight sequential patients receiving dual chamber pacemaker with DDD modality with cardiogenic shock and hemodynamic instability refractory to catecholamines underwent echocardiography-guided pacemaker optimization of cardiac output. An iterative method with Doppler echocardiography was used to assess changes in cardiac output, left ventricular filling time, ejection time, total isovolumic time, mitral regurgitation, ejection fraction, and blood pressure at different increments of heart rate, and atrioventricular and interventricular delay. All results are shown as median (minimum/maximum level) or mean ± SD. Using echocardiography-guided pacemaker optimization on cardiac output, the cardiac output increased from 3.2 (2.3/3.8) to 5.7 L/min (4.85/7.1) and cardiac index from 1.64 (1.1/1.9) to 2.68 L/min/m (2.1/3.2) and the total isovolumic time reduced from 22.8 to normal values (<14). In association, the glomerular filtration rate increased significantly except in one patient with stage IV chronic kidney disease. All inotropes and vasopressors were discontinued within 12 hours of pacemaker optimization on cardiac output, and all patients were discharged from the ICU within 1 week. Echocardiography-guided pacemaker optimization of cardiac output is a feasible bedside therapeutic option, which should be considered when standard medical treatments are insufficient for the treatment of cardiogenic shock refractory to inotropic support, thereby minimizing the detrimental effect of catecholamines.


Use of fibrin glue and gelfoam to repair collecting system injuries in a porcine model: implications for the technique of laparoscopic partial nephrectomy.
One of the challenges of laparoscopic partial nephrectomies is the repair of a collecting system injury. We hypothesized that fibrin glue plus Gelfoam could be sufficient to repair such injuries. Four pigs (eight kidneys) underwent collecting system injuries of various lengths (3, 5, and 10 mm) (N = 8 each) during partial nephrectomy. Gelfoam soaked in the fibrin glue was applied to seal the collecting system and parenchymal defects. After 1 hour of passive filling, the renal pelvis was distended at supraphysiologic pressure to the point of leakage. Each repair site was examined for urinary extravasation during the physiologic and active phases of filling. Hemostasis was achieved, and all collecting system injuries, regardless of size, were free of urinary leakage at physiologic pressures. Moreover, all defects maintained a seal at supraphysiologic pressures of at least 50 cm H(2)O. The combined use of fibrin glue and Gelfoam is an effective means to obtain hemostasis and seal collecting system injuries up to 10 mm at physiologic pressures and up to 50 cm H(2)O in the acute setting. Our hope is that this technique can facilitate both laparoscopic and open partial nephrectomies. New technologies will be employed in an attempt to obtain better seating of the sealant plug in the future. Survival studies are in progress.


Designing greener active pharmaceutical ingredients: Insights from pharmaceutical industry into drug discovery and development.
Active pharmaceutical ingredients (APIs), their metabolites and transformation products (TPs) are found as pollutants in the environment. They can impact human and environmental health. To address this issue, an efficient, long-term prevention strategy could be the design of APIs that have less impact on the natural environment, i.e. the design of greener APIs, by the implementation of environmental parameters into the drug discovery and development process (also abbreviated R&D for 'research and development'). Our study aimed to evaluate the feasibility of the design of greener APIs based on insights from drug design experts working in large, research-based pharmaceutical companies. The feasibility evaluation also identified needs and incentives for process modification. For this purpose, 30 R&D and environmental experts from seven globally active pharmaceutical companies were interviewed along a structured questionnaire. Main findings are that the interviewed experts saw manifold opportunities to include properties rendering APIs greener in different stages along the R&D process. This implementation would be favoured by the fact that the pharmaceutical R&D process is very flexible and relies on balancing multiple parameters. Furthermore, some API properties that reduce environmental risks were considered compatible with common desirable properties for application. Environmental properties should be considered early during R&D, i.e. when molecules are screened and optimized. It has been found that availability of suitable in silico models and in vitro assays is crucial for this environmental consideration. Their attributes, e.g. throughput and costs, determine at which process stage they can be successfully applied. An intensified exchange between R&D and environmental experts within and outside companies would push the industrial application of the benign by design approach for APIs forward. Collaboration across pharmaceutical companies, authorities, and academia is seen as highly promising in this respect. Financial, social, and regulatory incentives would support future design of greener APIs.


A case of Ganser's state presenting as a dementia syndrome.
We report an atypical case of Ganser's syndrome in a 54-year-old male patient. The following symptoms which include approximate answers perceptual disturbances and dissociative mechanisms were observed over 7 years, improved during hospitalization, but reappeared just before the patient's discharge. The extremely long presence and bizarre manifestation of symptoms, the course of the disorder and the patient's premorbid high intelligence level point to an unusual presentation of this case. Following the concept of hysteria and dissociation, we discuss its diagnosis within the scope of the DSM-III-R, DSM-IV and ICD-10 classification of Dissociative Disorders. Problems in the differential diagnosis which result from an increasing awareness of Dissociative Disorders are outlined.


Practitioner Review: Therapeutics of unipolar major depressions in adolescents.
Over the past two decades new and key randomized controlled trials have reported the efficacy, clinical and cost effectiveness of psychological and pharmacological treatments for adolescents with major depression. The literature was searched through pubmed, psychinfo, scopus and web of science for randomized controlled trials of current major depression together with meta-analyses and systematic reviews of trials between 2000 and 2017. Those specific to the adolescent years (11-18 years) were taken as the primary source for this narrative review. Additional selected studies in adults were used to illustrate methodological issues. Manualized psychological therapies and the SSRI fluoxetine are more effective than active placebo in the treatment of major depressions. Mild to moderate illnesses attending community-based services are likely to benefit from psychological treatment alone. Moderately to severely ill patients attending clinic and hospital services are likely to benefit from monotherapies or combining psychological and pharmacological treatment. Antidepressants carry a small but significant side-effect risk including increased suicidality. Side effects from psychotherapies are somewhat lower but specific negative consequences remain less well characterized. There is some evidence that CBT-based approaches prevent onset of major depression episode in well adolescents at high-risk. Other psychological interventions have not been adequately studied. There has been only limited identification of treatment moderators and no clear understanding of therapeutic mechanisms. There is now a range of clinically effective treatments for depressed adolescents. Future research needs to reveal moderators of and mechanisms for individual differences to treatment response, determine psychotherapies of value for milder depressions, enhance our understanding of safety and side-effects for all treatments, and consider how to reduce and treat treatment-resistant cases.